title: Rational development of a strategy for modifying the aggregatibility of proteins.
abstract: The conversion of peptide and proteins from their soluble state into well-organized aggregates, together with the accompanied oxidation of methionine residue, presents a significant challenge to human health, to the manufacture of protein therapeutics, and to the synthesis of proteins and glycoproteins. Despite their fundamental importance, little is known about the molecular basis of these two side reactions and their control. Here, using chemical peptide synthesis, we further confirmed the importance of the balance between hydrophobic interactions and electrostatic repulsive forces in inducing and inhibiting aggregation and methionine oxidation. Most importantly, through extending the established principle, we are able to effectively stabilize the problematic peptide fragment through the attachment of cleavable arginine tags. Future applications of our approach are expected to facilitate the synthesis and study of difficult peptides, proteins, and glycoproteins and will provide more opportunities for the optimization of protein biopharmaceuticals and for the development of cell-permeable biomolecules.
authors.affiliation: Bio-Organic Chemistry Laboratory, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Tan
authors.forename: Shiying
authors.initials: S
authors.lastname: Shang
authors.forename: Samuel J
authors.initials: SJ
authors.lastname: Danishefsky
mesh_terms: D000595:Amino Acid Sequence; D001671:Biochemistry / Q000379:methods*; D002853:Chromatography, Liquid; D004921:Erythropoietin / Q000737:chemistry; D006801:Humans; D013058:Mass Spectrometry; D008715:Methionine / Q000378:metabolism; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D010455:Peptides / Q000737:chemistry; D020836:Protein Structure, Quaternary; D011506:Proteins / Q000737:chemistry*
chemical_list: D010455:Peptides; D011506:Proteins; D004921:Erythropoietin; D008715:Methionine